Benzyl(Idene)-lactam derivatives, their preparation and their use as selective (ANT) agonists of 5-HT1A- and/or 5-HT1D receptors

ABSTRACT

The present invention relates to lactam derivatives of the formula 
                 
 
wherein R 1 , R 2 , R 3 , A, X, Z, n and the dashed line are defined herein, and pharmaceutical compositions thereof, to processes and intermediates for their preparation, and to their medicinal use as selective agonists and antagonists of serotonin 1 (5-HT 1 ) receptors, specifically, of one or both of the 5-HT 1A  and 5-HT 1D  receptors. These compounds are useful in treating or preventing migraine, depression and other disorders for which a 5-HT 1  agonist or antagonist is indicated.

This application is a division of Ser. No. 09/155,215, filed Sep. 24,1998, now U.S. Pat. No. 6,462,048, which is a National Stage under 35USC 371 of PCT/IB97/100076, filed Feb. 3, 1997, which claims the benefitof Ser. No. 60/015,134, filed Mar. 29. 1996.

BACKGROUND OF THE INVENTION

The present invention relates to lactam derivatives, to processes andintermediates for their preparation, to pharmaceutical compositionscontaining them and to their medicinal use. The compounds of the presentinvention include selective agonists and antagonists of serotonin 1(5-HT₁) receptors, specifically, of one or both of the 5-HT_(1A) and5-HT_(1D) receptors. They are useful in treating or preventing migraine,depression and other disorders for which a 5-HT₁ agonist or antagonistis indicated.

European Patent Publication 434,561, published on Jun. 26, 1991, refersto 7-alkyl, alkoxy, and hydroxysubstituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compoundsare referred to as 5-HT₁ agonists and antagonists useful for thetreatment of migraine, depression, anxiety, schizophrenia, stress andpain.

European Patent Publication 343,050, published on Nov. 23, 1989, refersto 7-unsubstituted, halogenated, and methoxysubstituted-1-(4substituted-1-piper-azinyl)-naphthalenes as useful5-HT_(1A) ligand therapeutics.

Glennon et al., refers to 7-methoxy-1-(1-piperazinyl)-naphthalene as auseful 5-HT₁ ligand in their article “5-HT_(1D) Serotonin Receptors”,Clinical Drug Res. Dev., 22, 25-36 (1991).

Glennon's article “Serotonin Receptors: Clinical Implications”,Neuroscience and Behavoral Reviews, 14, 35-47 (1990), refers to thepharmacological effects associated with serotonin receptors includingappetite suppression, thermoregulation, cardiovascular/hypotensiveeffects, sleep, psychosis, anxiety, depression, nausea, emesis,Alzheimers disease, Parkinsons disease and Huntingtons disease.

Ligands with high affinity for the 5-HT₁ receptors are well recognizedas having therapeutic value for the treatment of human conditions causedby serotonin imbalance.

World Patent Application WO 95/31988, published Nov. 30, 1995, refers tothe use of 5-HT_(1D) antagonist in combination with a 5-HT_(1A)antagonist to treat CNS disorders such depression, generalized anxiety,panic disorder, agoraphobia, social phobias, obsessive-compulsivedisorder, post-traumatic stress disorder, memory disorders, anorexianervosa and bulimia nervosa, Parkinson's disease, tardive dyskinesias,endocrine disorders such as hyperprolactinaemia, vasospasm (particularlyin the cerebral vasculature) and hypertension, disorders of thegastrointestinal tract where changes in motility and secretion areinvolved, as well as sexual dysfunction. G. Maura et al., J. Neurochem,66 (1), pp 203-209 (1996), have stated that administration of agonistsselective for 5-HT_(1A) receptors or for both 5-HT_(1A) and 5-HT_(1D)receptors might represent a great improvement in the treatment of humancerebellar ataxias, a multifaceted syndrome for which no establishedtherapy is available.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula I, depictedbelow,

wherein R¹ is a group of the formula G¹, G², G³, G⁴ or G⁵, depictedbelow,

wherein E is oxygen, sulfur, SO or SO₂;

R⁶and R⁷ are independently selected from hydrogen, (C₁-C₅) alkyl,[(C₂-C₄)alkyl]aryl wherein the aryl moiety is phenyl or naphthyl, andheteroaryl-(CH₂)_(q) wherein the heteroaryl moiety is selected frompyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl andbenzisothiazolyl and q is zero, one, two, three or four, and whereinsaid aryl and heteroaryl moieties may optionally be substituted with oneor more substituents, preferably from zero to three substituents,independently selected from chloro, fluoro, bromo, iodo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, trifluoromethyl, cyano and SO_(g)(C₁-C₆)alkyl wherein gis zero, one or two;

or R⁶ and R⁷ together form a 2 to 4 carbon chain;

x is zero to eight;

each R¹³ is, independently, (C₁-C₄)alkyl or a (C₁-C₄)methylene bridgefrom one of the ring carbons of the piperazine or piperidine ring of G¹or G², respectively, to the same or another ring carbon or a ringnitrogen of the piperizine or piperidine ring of G¹ or G², respectively,having an available bonding site, or to a ring carbon of R⁶ having anavailable bonding site;

R⁸ is selected from hydrogen and (C₁-C₃) alkyl;

R⁹ is selected from hydrogen and (C₁-C₆)alkyl;

or R⁶ and R⁹, together with the nitrogen atom to which they areattached, form a 5 to 7 membered ring;

and p is one, two, or three;

R² is hydrogen, (C₁-C₄)alkyl, phenyl or naphthyl, wherein said phenyl ornaphthyl may optionally be substituted with one or more substituents,preferably from zero to three substituents, independently selected fromchloro, fluoro, bromo, iodo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,trifluoromethyl, cyano and SO_(g)(C₁-C₆)alkyl wherein g is zero, one ortwo;

R³ is (CH₂)_(m)B, wherein m is zero, one, two or three and B ishydrogen, phenyl, naphthyl or a 5 or 6 membered heteroaryl groupcontaining from one to four hetero atoms in the ring (e.g., furyl,thienyl, pyridyl, pyrimidyl, thiazolyl, pyrazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl,etc.), and wherein each of the foregoing aryl and heteroaryl groups mayoptionally be substituted with one or more substituents, preferably fromzero to three substituents, independently selected from chloro, fluoro,bromo, iodo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, cyano,hydroxy, COOH and SO_(g)(C₁-C₆)alkyl wherein g is zero, one or two;

Z is CR⁴R⁵, wherein R⁴ and R⁵ are independently selected from hydrogen,(C₁-C₆)alkyl and trifluoromethyl; or Z may be one of the aryl orheteroaryl groups referred to in the definition of B above and whereintwo adjacent ring members of Z are also members of ring A;

X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C₁-C₆)alkyl,hydroxy, trifluoromethyl, (C₁-C₆)alkoxy, —SO_(g)(C₁-C₆)alkyl wherein gis zero one or two, CO₂R¹⁰ or CONR¹¹R¹²;

each of R¹⁰, R¹¹ and R¹² is selected, independently, from the radicalsset forth in the definition of R²; or R¹¹ and R¹², together with thenitrogen to which they are attached, form a 5 to 7 membered ring thatmay contain from zero to four heteroatoms selected from nitrogen, sulfurand oxygen, for example, where NR¹¹R¹² is pyrrolidinyl, pyrrolyl,imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl, morpholinyl,thiomorpholinyl, hexamethyleneiminyl, diazepinyl,oxazopinyl,thiazepinyl, oxadiazepinyl, thiadiazopinyl or triazepinyl;

n is one, two, three or four; and

the broken line indicates an optional double bond;

with the proviso that n must be one when Z is an aryl or heteroarylgroup;

and the pharmaceutically acceptable salts thereof.

The following are more specific embodiments of groups G¹ and G².

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formula I. The acids which areused to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate,lactate, citrate, acid citrate, tartrate, bitartrate, succinate,maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

The invention also relates to base addition salts of formula I. Thechemical bases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those compounds of formula I that are acidic innature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to those derivedfrom such pharmacologically acceptable cations such as alkali metalcations (e.g., potassium and sodium) and alkaline earth metal cationse., calcium and magnesium), ammonium or water-soluble amine additionsalts such as N-methylglucamine-(meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines.

The compounds of this invention include all stereoisomers and alloptical isomers of compounds of the formula I (e.g., R and Senantiomers), as well as racemic, diastereomeric and other mixtures ofsuch isomers.

Unless otherwise indicated, the alkyl and alkenyl groups referred toherein, as well as the alkyl moieties of other groups referred to herein(e.g., alkoxy), may be linear or branched, and they may also be cyclic(e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linearor branched and contain cyclic moieties. Unless otherwise indicated,halogen includes fluorine, chlorine, bromine, and iodine.

Preferred compounds of the formula I include those wherein R¹ ispiperazinyl.

Preferred compounds of the formula I also include those wherein Z isCH₂.

Preferred compounds of the formula I also include those wherein n is twoor three.

Preferred compounds of the formula I also include those where in R³ issubstituted phenyl.

Examples of specific preferred compounds of the formula I are thefollowing:

3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1,3-dihydro-indol-2-one;

6-chloro-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1,3-dihydro-indol-2-one;

5-chloro-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1,3-dihydro-indol-2-one;

1-methyl-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1,3-dihydro-indol-2-one;

3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1-phenyl-1,3-dihydro-indol-2-one;

1-(3,4-dichlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one;

1-(3,4-dichlorobenzyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1,3-dihydro-indol-2-one;

1-(4-chlorobenzyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one;

1-(4-chlorobenzyl)-3-[5-fluoro-2-(4-methylpiperazin-1yl)-benzylidene]-pyrrolidin-2-one;

1-(3,4-difluorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one;

1-(2,4-dichlorobenzyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one;

1-(3,4-dichlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one;

1-(4-chlorobenzyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one;

1-(3,4-dichlorobenzyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one;

1-(4-chlorophenyl)-3-[5fluoro-2-(4methylpiperazin-1-yl)-benzylidene]-piperidin-2-one;

1-(3,4-dichlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one;

3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1-phenyl-pyrrolidin-2-one;

3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1-(4-trifluoromethylphenyl)-pyrrolidin-2-one;

1-(3,4-difluorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzyl]-pyrrolidin-2-one;

3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one;

3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one;

3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one;

1-(3,4-dichlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzyl]-piperidin-2-one;

1-(4-methoxyphenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-3,4-dihydro-1H-quinolin-2-one;

1-(3,4-dichlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzyl)-piperidin-2-one;

3-[2-(4-methylpiperazin-1-yl)-benzyl]-1-phenyl-pyrrolidin-2-one;

3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1-(p-tolyl)-pyrrolidin-2-one;

3-[4-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-1-phenyl-pyrrolidin-2-one;

1-(3,4-dichlorophenyl)-3-[2-fluoro-6-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one;

1-(3,4-difluorophenyl)-3-[5-fluoro-2-(4methylpiperazin-1-yl)-benzylidene]-piperine-2-one;

1-[2-(4-chlorophenyl)ethyl]-3-[5-fluoro-2-(4methylpiperazin-1-yl)-benzylidene]-piperidin-2-one;

1-(3,4-dichlorophenyl)-3-[2-(2-dimethylaminoethoxy)-benzylidene]-pyrrolidin-2-one;and

3-[2-(4-methylpiperazin-1-yl)-benzyl]-1-(4-trifluoromethylphenyl)-pyrrolidin-2-one.

Other compounds of formula I include the following:

1-(3,4-dichlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-azetidin-2-one;

1-(3,4-dichlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-azepin-2-one;

1-(3,4-dichlorophenyl)-3-{1-[2-(4methylpiperazin-1-yl)phenyl]ethyl}-pyrrolidin-2-one;

1-(3,4-dichlorophenyl)-3-{1-[2-(4-methylpiperazin-1-yl)phenyl]ethyl-piperidine-2-one;

1-(3,4-dichlorophenyl)-3-{1-[2-(4-methylpiperazin-1-yl)phenyl]-ethylidene}-pyrrolidin-2-one;

1-(3,4-dichlorophenyl)-3-{1-[2-(4-methylpiperazin-1-yl)phenyl]-ethylidene}-piperidin-2-one;

1-(3,4-dichlorophenyl)-3-{[2-(4-methylpiperazin-1-yl)phenyl]-phenylmethylene}-pyrrolidin-2-one;

1-(3,4-dichlorophenyl)-3-{2-[(2-dimethylaminoethyl)-methylamino]-benzylidene}-pyrrolidin-2-one;

1-(3,4-dichlorophenyl)-3-[2-(pyrrolidin-1-ylethoxy)-benzylidene]-pyrrolidin-2-one;

1-(3,4-dichlorophenyl)-3-[2-(2-dimethylaminoethylamino)-benzylidene]-pyrrolidin-2-one;

2-(3,4-dichlorophenyl)-3-[2-(2-dimethylaminoethylamino)-benzylidene]-pyrrolidin-2-one;

2-(3,4-dichlorophenyl)-4-[2-(4-methylpiperazin-1-yl)-benzylidene]-octahydro-isoquinolin-3-one;

1-(3,4-dichlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-octahydro-quinolin-2one;

1-(3,4-dichlorophenyl)-3-[2-(4methylpiperazin-1-yl))-benzylidene]-octahydro-indol-2-one; and

1-(3,4-dichlorophenyl)-5,5-dimethyl-3-[2-(4methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition selected fromhypertension, depression, generalized anxiety disorder, phobias e.g.,agoraphobia, social phobia and simple phobias), posttraumatic stresssyndrome, avoidant personality disorder, premature ejaculation, eatingdisorders (e.g., anorexia nervosa and bulimia nervosa), obesity,chemical dependencies (e.g., addictions to alcohol, cocaine, heroin,phenolbarbitol, nicotine and benzodiazepines), cluster headache,migraine, pain, Alzheimer's disease, obsessive-compulsive disorder,panic disorder, memory disorders (e.g., dementia, amnestic disorders,and age-associated memory impairment), Parkinson's diseases (e.g.,dementia in Parkinson's disease, neuroleptic-induced parkinsonism andtardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia),vasospasm (particularly in the cerebral vasculature), cerebellar ataxia,gastrointestinal tract disorders involving changes in motility andsecretion, and chronic paroxysmal hemicrania and headache associatedwith vascular disorders in a mammal, preferably a human, comprising anamount of a compound of the formula I or a pharmaceutically acceptablesalt thereof effective in treating or preventing such disorder orcondition and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition that can be treated orprevented by enhancing serotonergic neurotransmission in a mammal,preferably a human, comprising an amount of a compound of the formula I,or a pharmaceutically acceptable salt thereof, effective in treating orpreventing such disorder or condition and a pharmaceutically acceptablecarrier. Examples of such disorders and conditions are those enumeratedin the preceding paragraph.

The present invention also relates to a method for treating orpreventing a disorder or condition selected from hypertension,depression, generalized anxiety disorder, phobias (e.g., agoraphobia,social phobia and simple phobias), posttraumatic stress syndrome,avoidant personality disorder, premature ejaculation, eating disorders(e.g., anorexia nervosa and bulimia nervosa), obesity, chemicaldependencies (e.g., addictions to alcohol, cocaine, heroin,phenolbarbitol, nicotine and benzodiazepines), cluster headache,migraine, pain, Alzheimer's disease, obsessive-compulsive disorder,panic disorder, memory disorders (e.g., dementia, amnestic disorders,and age-associated memory impairment), Parkinson's diseases (e.g.,dementia in Parkinson's disease, neuroleptic-induced parkinsonism andtardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia),vasospasm (particularly in the cerebral vasculature), cerebellar ataxia,gastrointestinal tract disorders involving changes in motility aridsecretion, and chronic paroxysmal hemicrania and headache associatedwith vascular disorders in a mammal, preferably a human, comprisingadministering to a mammal in need of such treatment or prevention anamount of a compound of the formula I, or a pharmaceutically acceptablesalt thereof, that Is effective in treating or preventing such disorderor condition.

The present invention also relates to a method for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, preferably ahuman, comprising administering to a mammal in need of such treatment orprevention an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, that is effective in treatingor preventing such disorder or condition.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition selected fromhypertension, depression, generalized anxiety disorder, phobias (e.g.,agoraphobia, social phobia and simple phobias), posttraumatic stresssyndrome, avoidant personality disorder, premature ejaculation, eatingdisorders (e.g., anorexia nervosa and bulimia nervosa), obesity,chemical dependencies e.g., addictions to alcohol, cocaine, heroin,phenolbarbitol, nicotine and benzodiazepines), cluster headache,migraine, pain, Alzheimer's disease, obsessive-compulsive disorder,panic disorder, memory disorders (e.g., dementia, amnestic disorders,and age-associated memory impairment), Parkinson's diseases (e.g.,dementia in Parkinson's disease, neuroleptic-induced parkinsonism andtardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia),vasospasm (particularly in the cerebral vasculature), cerebellar ataxia,gastrointestinal tract disorders involving changes in motility andsecretion, and chronic paroxysmal hemicrania and headache associatedwith vascular disorders in a mammal, preferably a human, comprising aserotonin receptor antagonizing or agonizing effective amount of acompound of the formula I, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition that can be treated orprevented by enhancing serotonergic neurotransmission in a mammal,preferably a human, comprising a serotonin receptor antagonizing oragonizing effective amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The present Invention also relates to a method for treating orpreventing a disorder or condition selected from hypertension,depression, generalized anxiety disorder, phobias (e.g., agoraphobia,social phobia and simple phobias), posttraumatic stress syndrome,avoidant personality disorder, sexual dysfunction (e.g., prematureejaculation), eating disorders (e.g., anorexia nervosa and bulimianervosa), obesity, chemical dependencies (e.g., addictions to alcohol,cocaine, heroin, phenolbarbitol, nicotine and benzodiazepines), clusterheadache, migraine, pain, Alzheimer's disease, obsessive-compulsivedisorder, panic disorder, memory disorders (e.g., dementia, amnesticdisorders, and age-associated memory impairment), Parkinson's diseases(e.g., dementia in Parkinson's disease, neuroleptic-induced parkinsonismand tardive dyskinesias), endocrine disorders (e.g.,hyperprolactinaemia), vasospasm (particularly in the cerebralvasculature), cerebellar ataxia, gastrointestinal tract disordersinvolving changes in motility and secretion, and chronic paroxysmalhemicrania and headache associated with vascular disorders in a mammal,preferably a human, comprising administering to a mammal requiring suchtreatment or prevention a serotonin receptor antagonizing or agonizingeffective amount of a compound of the formula I or a pharmaceuticallyacceptable salt thereof.

The present invention also relates to a method for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, preferably ahuman, comprising administering to a mammal requiring such treatment orprevention a serotonin receptor antagonizing or agonizing effectiveamount of a compound of the formula I or a pharmaceutically acceptablesalt thereof.

The present invention relates to a pharmaceutical composition fortreating or preventing a condition or disorder that can be treated orprevented by enhancing serotonergic neurotransmission in a mammal,preferably a human, comprising:

a) a pharmaceutically acceptable carrier;

b) a compound of the formula I or a pharmaceutically acceptable saltthereof; and

c) a 5-HT re-uptake inhibitor, preferably sertraline, or apharmaceutically acceptable salt thereof;

wherein the amount of the active compounds (i.e., the compound offormula I and the 5-HT re-uptake inhibitor) are such that thecombination is effective in treating or preventing such disorder orcondition.

The present invention also relates to a method for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, preferably ahuman, comprising administering to a mammal requiring such treatment orprevention:

a) a compound of the formula I, defined above, or a pharmaceuticallyacceptable salt thereof; and

b) a 5-HT re-uptake inhibitor, preferably sertraline, or apharmaceutically acceptable salt thereof;

wherein the amounts of the active compounds (i.e., the compound offormula I and the 5-HT re-uptake inhibitor) are such that thecombination is effective in treating or preventing such disorder orcondition.

The present invention also relates to a method for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, preferably ahuman, comprising administering to said mammal requiring such treatmentor prevention:

a) a 5-HT_(1A) antagonist or a pharmaceutically acceptable salt thereof;and

b) a 5-HT_(1D) antagonist or a pharmaceutically acceptable salt thereof;

wherein the amounts of each active compound (i.e., the 5-HT_(1A)antagonist and the 5-HT_(1D) antagonist) are such that the combinationis effective in treating or preventing such disorder or condition.

“Enhanced serotonergic neurotransmission,” as used herein, refers toincreasing or improving the neuronal process whereby serotonin isreleased by a pre-synaptic cell upon excitation and crosses the synapseto stimulate or inhibit the post-synaptic cell.

“Chemical dependency,” as used herein, means an abnormal craving ordesire for, or an addiction to a drug. Such drugs are generallyadministered to the affected individual by any of a variety of means ofadministration, including oral, parenteral, nasal or by inhalation.Examples of chemical dependencies treatable by the methods of thepresent invention are dependencies on alcohol, nicotine, cocaine,heroin, phenolbarbitol, and benzodiazepines (e.g., Valium (trademark)).“Treating a chemical dependency,” as used herein, means reducing oralleviating such dependency.

Sertraline,(1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4tetrahydro-N-methyl-1-naphthalenamine,as used herein has the chemical formula C₁₇H₁₇NCl₂ and the followingstructural formula

Its synthesis is described in U.S. Pat. No. 4,536,518, assigned toPfizer Inc. Sertraline hydrochloride is useful as an antidepressant andanorectic agent, and is also useful in the treatment of depression,chemical dependencies, anxiety obsessive compulsive disorders, phobias,panic disorder, post traumatic stress disorder, and prematureejaculation.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the formula I may be prepared according to the followingreaction schemes and discussion. Unless otherwise indicated, R¹ throughR¹², G¹ through G⁵, X, A, B, E, Z, n, m, p, q, and g and structuralformula I in the reaction schemes and discussion that follow are asdefined above.

Scheme 1 illustrates a method of synthesizing compounds of the formula Iwherein the dashed line represents a double carbon-carbon bond and R¹ isa group of the formula G¹, G³, G⁴ or G⁵. Referring to Scheme 1, acompound of the formula II, wherein Q is a suitable leaving group (e.g.,chloro, fluoro, bromo, mesylate, tosylate, etc.), is reacted with acompound of the formula R¹H, wherein R¹ is a group of the formula G¹,G³, G⁴ or G⁵, in the presence of a base, to form the correspondingcompound of formula III. This reaction is generally carried out at atemperature from about 0° C. to about 140° C., preferably at about thereflux temperature, in a polar solvent such as dimethyl sulfoxide(DMSO), N,N dimethylformamide (DMF), N,N-dimethylacetamide (DMA) orN-methyl-2-pyrrolidinone (NMP), preferably DMF. Suitable bases includeanhydrous sodium carbonate (Na₂CO₃), potassium carbonate (K₂CO₃), sodiumhydroxide (NaOH) and potassium hydroxide (KOH), as well as tertiaryamines such as pyrrolidine, triethylamine and pyridine. Anhydrouspotassium carbonate is preferred.

Compounds of formula III can be converted into compounds of the formulaI wherein R³ is other than hydrogen (i.e., compounds of the formula IB,as depicted In Scheme 1), by subjecting them to an Aldol condensation orWittig reaction. For example, in the case of an Aldol condensation, acompound of the formula III can be reacted with a compound of theformula

in the presence of a base, to form an aldol intermediate of the formulaV, which may be isolated or converted directly in the same reaction stepto a compound of the formula IB by the loss of water. The degree ofcompletion for the conversion of compounds of the formula III to thealdol product of formula IB may be assessed using one or more analyticaltechniques, such as thin layer chromatography (tlc) or massspectrometry. In some instances it may be possible or desirable toisolate the intermediate of formula V. In such case, the compound offormula V may be converted into the compound of formula IB by theelimination of water using techniques which are familiar to thoseskilled in the art, for example, by heating to the reflux temperature asolution of the compound of formula V in a solvent such as benzene,toluene or xylene, in the presence of a catalytic amount of benzene- orp-toluene-sulfonic acid with provision for the removal of the watergenerated. Such water removal techniques may involve the use ofmolecular sieves or a Dean-Stark trap to isolate the water created as anazeotrope with the solvent.

The aldol reaction is typically carried out in a polar solvent such asDMSO, DMF, tetrahydrofuran (THF), methanol or ethanol, at a temperaturefrom about −25° C. to about 80° C. Preferably, this reaction is carriedout in THF at about 25° C. Suitable bases for use in the aldol formationstep include K₂CO₃, Na₂CO₃, sodium hydride (NaH), pyrrolidine andpiperidine. Sodium hydride is preferred. Aldol condensations aredescribed in “Modem Synthetic Reactions,” Herbert O. House, 2d. Edition,W. A. Benjamin, Menlo Park, Calif. 1972, pp. 629-682.

Compounds of the formula I wherein R³ is hydrogen (compounds of theformula IA, as depicted in Scheme 1) can be prepared via an Aldolcondensation in a manner analogous to that described above for theformation of compounds of the formula IB, but using as the startingmaterial a compound of the formula IV wherein R³ is hydrogen or—C(═O)R¹³ wherein R¹³ is (C₁-C₆)alkyl or trifluoromethyl. Compounds ofthe formula IA may be converted into compounds of the formula IB byreacting them with a compound of the formula R³Y wherein Y is a leavinggroup and is defined as Q is defined as above. These reactions can becarried out In a solvent such as di-(alkyl)ether, THF, DMF, DMA or DMSO,preferably DMF, in the presence of a base such as potassium carbonate,sodium carbonate, sodium hydride, potassium hydride, sodium hydroxide orpotassium hydroxide, preferably sodium hydride. Reaction temperaturescan range from about 0° C. to about 150° C., preferably from about 25°C. to about the reflux temperature of the solvent.

Alternatively, the compound of formula IV can be converted into acompound of the formula IB by means of a Wittig olefination, asdescribed in Helvetica Chimica Acta. 1963, 46, 1580 and depicted below.

Thus, the compound of formula IV can be converted into the correspondingbromide of formula XI using standard bromination conditions, followed bytreatment with triphenylphosphine in anhydrous THF to form theintermediate of formula XII. The compound of formula XII can then betreated with a strong base (e.g., aqueous Na₂CO₃) to generate thecorresponding phosphonium ylide, which can then be reacted with theappropriate intermediate of formula III to produce compounds of generalformula I. This transformation is described in A. Maercker, OrganicReactions, 1965, 14, 270.

Compounds of the formula I wherein the dashed line represents a singlecarbon-carbon bond may be prepared by hydrogenating the correspondingcompounds wherein the dashed line represents a double carbon-carbonbond, using standard techniques that are well known to those skilled inthe art. For example, reduction of the double bond may be effected withhydrogen gas (H₂), using catalysts such as palladium on carbon (Pd/C),palladium on barium sulfate (Pd/Ba₂SO₄), platinum on carbon (PVC), ortris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), in anappropriate solvent such as methanol, ethanol, THF, dioxane or ethylacetate, at a pressure from about 1 to about 5 atmospheres and atemperature from about 10° C. to about 60° C., as described in CatalyticHydrogenation in Organic Synthesis, Paul Rylander, Academic Press Inc.,San Diego, 1979, pp. 31-63. The following conditions are preferred: Pdon carbon, methanol at 25° C. and 50 psi of hydrogen gas pressure. Thismethod also provides for introduction of hydrogen isotopes (i.e.,deuterium, tritium) by replacing ¹H₂ with ²H₂ or ³H₂ in the aboveprocedure.

An alternative procedure employing the use of reagents such as ammoniumformate and Pd/C in methanol at the reflux temperature under an inertatmosphere (e.g., nitrogen or argon gas) is also effective in reducingthe carbon-carbon double bond of compounds of the formula I. Anotheralternative method involves selective reduction of the carbon-carbondouble bond using samarium and iodine or samarium iodide (SmI₂) inmethanol or ethanol at about room temperature, as described by R. Yanadaet. al., Synlett., 1995, pp 443-4.

The starting materials of the formulas II and IV are either commerciallyavailable or known in the art. For example, compounds of formula II inwhich R² is hydrogen are readily available from commercial sources ormay be prepared using procedures disclosed in the chemical literature.They may also be prepared from the corresponding carboxylic acids oresters (i.e., formula II wherein R²═OH or O-alkyl), which arecommercially available. These acids or esters can be reduced to thecorresponding alcohols of formula XIII, depicted below, wherein Q isdefined as for formula II, using one or more of a variety of reducingagents and conditions, depending upon the nature of the substituents Qand X.

Such reducing agents include sodium borohydride (NaBH₄), sodiumcyanoborohydride (NaCNBH₃), lithium aluminum hydride (LiAlH₄) and boranein THF (BH₃·THF) in solvents such as methanol, ethanol, THF, diethylether and dioxane. Oxidation of the alcohol of formula XIII to thecorresponding aldehyde of formula II may be accomplished using aselective oxidizing agent such as Jones reagent (hydrogen chromate(H₂CrO₄)), pyridinium chlorochromate (PCC) or manganese dioxide (MnO₂).References for such conversions are readily available (e.g. K. B.Wiberg, Oxidation in Organic Chemistry, Part A, Academic Press Inc, N.Y.1965, pp. 69-72).

The starting materials of formula IV can be prepared by several methods,including procedures disclosed in the literature. For example, thecompounds of formula IV wherein Z is an aromatic ring and n=1 (i.e.,1,3-dihydro-indol-2-one and substituted analogs thereof) are accessiblecommercially or may be prepared using methods disclosed in, e.g., H. R.Howard and R. Sarges, U.S. Pat. No. 4,476,307, Oct. 9, 1984. One methodof preparing the starting materials of formula IV wherein Z is CR⁴R⁵ andn is one, two or three involves the condensation of a cyclic lactone ofthe formula VII with an amine of the formula H₂NR³, as shown below, inthe presence of a strong mineral acid such as hydrochloric acid (HCl).(See M. J. Kornet, J. Pharm. Sci., 1979, 68(3), 350; and J. Het. Chem.,1966, 3, 311).

Alternatively, compounds of the formula IV wherein R³ is hydrogen(compounds of the formula IVA) may be alkylated to form thecorresponding compounds wherein R³ is not hydrogen (compounds of theformula IB) using standard techniques available to those skilled in theart, e.g., by (a) generation of the anion of the desired compound offormula IVA using a strong base/polar solvent system such as NaH/THF,NaH/DMF or n-butyllithium/THF (n-buLi/THF), at a temperature from about−30° C. to about the reflux temperature of the solvent, for a period ofabout 5 minutes to about 24 hours, and (b) treatment of the anion withan alkylating agent of the formula R³Y wherein Y is a leaving group suchas chloro, bromo, iodo or mesylate. This process Is depicted below.

The foregoing conversion of compounds of the formula IVA to those of theformula IVB may also be achieved using phase transfer catalysisconditions as described by Takahata et al., Heterocycles, 1979, 12(11),pp. 1449-1451.

The compounds of formula R¹H used in the preparation of intermediates ofthe formula III are readily available or may be prepared using standardmethods of organic synthesis known to those skilled in the art andadapted from procedures disclosed in the chemical literature. Forexample, the preparation of compounds of the formula R¹H, wherein R¹ isG¹, may be accomplished using the following reaction sequence, beginningwith commercially available N-tert-butoxycarbonyl piperazine (VI):

Alkylation of the compound of formula VI with a compound of the formulaR⁶Y wherein Y is defined as above and R⁶ is (C₁-C₆)alkyl,aryl-(C₂-C₄)alkyl wherein the aryl moiety Is phenyl or naphthyl, orheteroaryl-(CH₂)_(q), wherein q is zero, one, two, three or four, andthe heteroaryl moiety is selected from pyridyl, pyrimidyl, benzoxazolyl,benzothiazolyl, benzisoxazolyl, and benzisothiazolyl, in the presence ofan acid scavenger (e.g., sodium bicarbonate (NaHCO₃), potassiumbicarbonate (KHCO₃), sodium carbonate (Na₂CO₃) or potassium carbonate(K₂CO₃)), in a polar solvent such as acetone at a temperature of about10° C. to about the reflux temperature of the solvent, will yield theintermediate of formula VII. Removal of the tert-butoxy-carbonyl groupcan be accomplished using acidic conditions, e.g., HBr in acetic acid ortrifluoroacetic acid until the reaction is judged to be complete.

Compounds of the formula III wherein R¹ is tetrahydropyridine orpiperidine and R² is hydrogen can be prepared from 2-bromobenzaldehyde,which is commercially available, as depicted in Scheme 2. Referring toScheme 2, the compound of formula II is first converted into a protectedaldehyde or ketone of the formula XIV, wherein P represents the entireprotected aldehyde or ketone moiety, using methods well known in theart. For example, the 1,3-dioxolane derivative of the aldehyde or ketonemay be prepared according to the method described by J. E. Cole et al.J. Chem. Soc., 1962, pp 244, by refluxing a solution of the aldehyde offormula II and 1,3-propanediol in anhydrous benzene with a catalyticamount of p-toluenesulfonic acid. When R² of formula II is not hydrogen,the ketone can be protected using an appropriate protecting group.Appropriate protecting groups can be chosen from many such groups basedon the presence and nature of the substituent X. Examples of suitableprotecting groups may be found in T. W. Greene, Protecting Groups InOrganic Synthesis, John Wiley & Sons, New York, 1981. The most preferredprotecting groups are those that are resistant to catalytichydrogenation (e.g., 1,3-dioxolane), which would therefore allow for thesubsequent reduction, if required, of the carbon-carbon double bond ofthe tetrahydropyridines of formula XVI.

Compounds of the formula XIV can then be treated with vinylstannanes ofthe formula XV, for example,1-BOC-4-trimethylstannyl-1,2,5,6-tetrahydropyridine(BOC=tert-butyloxycarbonyl), in the presence of a catalyst, to form thecorresponding compound of formula XVIA. Palladium is the preferredcatalyst (for example, (PH₃P)₄Pd or Pd₂(dba)₃), whereindba=dibenzylideneacetone. This reaction may be carried out as describedIn “Palladium-catalyzed Vinylation of Organic Halides” In OrganicReactions, Vol 27, pp. 345-390, W. G. Dauben, Ed., John Wiley & Sons,Inc., New York, N.Y., 1982.

Compounds of formula III where R¹ is piperidine (G²) can be prepared bycatalytic hydrogenation of the tetrahydropyridine of formula XVIA fromthe previous paragraph using standard methods known in the art,generally using palladium on carbon as the catalyst, to form thecorresponding compounds of formula XVIB. This reaction is typicallyperformed in an inert solvent, such as ethanol or ethyl acetate, eitherwith or without a protic acid such as acetic acid or HCl. Acetic acid ispreferred. The protecting groups on G² (i.e., BOC) can be removed usingone or more of the techniques described In Greene, referred to above,for example, stirring the compound of formula XVI in ethyl acetate and3M hydrochloric acid at about room temperature for about 30 minutes. Theprotecting group for the aldehyde or ketone, P, can be converted intothe unprotected ketone or aldehyde of the formula —C(═O)R² using one ormore of the techniques described in Greene, for example, stirring asolution of the compound of formula XVI in THF and 5% hydrochloric acidat room temperature for 20 hours.

Compounds of the formula XIV from the previous reaction scheme may alsobe treated with alkyllithium reagents, for example butyllithium,sec-butyllithium or tert-butyllithium, preferably butyllithium in aninert solvent, as shown in Scheme 3, to form the intermediate lithiumanion of formula XVII. Suitable solvents for this reaction include, forexample, ether or tetrahydrofuran, preferably tetrahydrofuran. Reactiontemperatures can range from about −110° C. to about 0° C. Theintermediate lithium anions of formula XVII can then be further reactedwith a suitable electrophile, selection of which depends on the presenceand nature of the substituent. Suitable electrophiles for use inpreparing compounds of the formula III wherein R¹ is a group of theformula G² include, for example, carbonyl derivatives or alkylatingagents (e.g., 1-BOC-4-piperidone). In the case where an aldehyde orketone is used as the electrophile, the hydroxy group must be removedfrom the intermediate of formula XVIII, as depicted below, in order toform the corresponding compound of formula III.

This step may be accomplished by one of several standard methods knownin the art. For example, a thiocarbonyl derivative such as a xanthatemay be prepared and removed by free radical processes, both of which areknown to those skilled In the art. Alternatively, the hydroxyl group maybe removed by reduction with a hydride source such as triethysilaneunder acidic conditions, using, for example, trifluoroacetic acid orboron trifluoride. The reduction reaction can be performed neat or in asolvent such as methylene chloride. A further alternative would be tofirst convert the hydroxyl group to a suitable leaving group, such astosylate or chloride, using standard methods known in the art, and thento remove the leaving group with a nucleophilic hydride, such as, forexample, lithium aluminum hydride. The latter reaction is typicallyperformed in an inert solvent such as ether or tetrahydrofuran. Also, areducing agent may be used to reductively remove the benzylicsubstituent. Suitable reducing agents include, for example, Raney nickelin ethanol and sodium or lithium in liquid ammonia. Another alternativemethod for removing the hydroxyl group is to first dehydrate the alcoholof formula XVIII to an olefin with a reagent such as Burgess salt (J.Org. Chem., 1973, 38, 26) and then to catalytically hydrogenate thedouble bond under standard conditions with a catalyst such as palladiumon carbon, The alcohol may also be dehydrated to the olefin by treatmentwith acid such as p-toluenesulfonic acid.

Compounds of the formula III wherein R¹ is G² and R⁶ is hydrogen can beconverted into the corresponding compounds of the formula III wherein R¹is G² and R⁶ is other than hydrogen by reacting them with a compound ofthe formula R⁶Y, as described above for preparing compounds of theformula VII.

Unless indicated otherwise, the pressure of each of the above reactionsis not critical. Generally, the reactions will be conducted at apressure of about one to about three atmospheres, preferably at ambientpressure (about one atmosphere).

The compounds of the formula I which are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toInitially isolate a compound of the formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent, and subsequently convert the free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this Invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the base compounds of this invention are those whichform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3naphthoate)] salts.

Those compounds of the formula I which are also acidic in nature, e.g.,where R³ includes a COOH or tetrazole moiety, are capable of formingbase salts with various pharmacologically acceptable cations. Examplesof such salts include the alkali metal or alkaline-earth metal saltsand, particularly, the sodium and potassium salts. These salts are allprepared by conventional techniques. The chemical bases which are usedas reagents to prepare the pharmaceutically acceptable base salts ofthis invention are those which form non-toxic base salts with the hereindescribed acidic compounds of formula I. These non-toxic base saltsinclude those derived from such pharmacologically acceptable cations assodium, potassium, calcium and magnesium, etc. These salts can easily beprepared by treating the corresponding acidic compounds with an aqueoussolution containing the desired pharmacologically acceptable cations,and then evaporating the resulting solution to dryness, preferably underreduced pressure. Alternatively, they may also be prepared by mixinglower alkanolic solutions of the acidic compounds and the desired alkalimetal alkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometricquantities of reagents are preferably employed in order to ensurecompleteness of reaction and maximum product yields.

Compounds of the formula I and their pharmaceutically acceptable salts(hereinafter also referred to, collectively, as “the active compounds”)are useful psychotherapeutics and are potent agonists and/or antagonistsof the serotonin 1A (5HT_(1A)) and/or serotonin ID (5-HT_(1D))receptors. The active compounds are useful in the treatment ofhypertension, depression, generalized anxiety disorder, phobias (e.g.,agoraphobia, social phobia and simple phobias), posttraumatic stresssyndrome, avoidant personality disorder, sexual dysfunction (e.g.,premature ejaculation), eating disorders (e.g., anorexia nervosa andbulimia nervosa), obesity, chemical dependencies (e.g., addictions toalcohol, cocaine, heroin, phenolbarbitol, nicotine and benzodiazepines),cluster headache, migraine, pain, Alzheimer's disease,obsessive-compulsive disorder, panic disorder, memory disorders (e.g.,dementia, amnestic disorders, and age-associated memory impairment),Parkinson's diseases (e.g., dementia in Parkinson's disease,neuroleptic-induced parkinsonism and tardive dyskinesias), endocrinedisorders (e.g., hyperprolactinaemia), vasospasm (particularly in thecerebral vasculature), cerebellar ataxia, gastrointestinal tractdisorders involving changes in motility and secretion, and chronicparoxysmal hemicrania and headache associated with vascular disorders.These compounds are also useful as vasodilators.

The affinitie of the compounds of this invention for the variousserotonin-1 receptors can be determined using standard radioligandbinding assays as described in the literature. The 5HT_(1A) affinity canbe measured using the procedure of Hoyer et al. (Brain Res., 1986, 376,85). The 5-HT_(1D) affinity can be measured using the procedure ofHeuring and Peroutka (J. Neurosci., 1987, 7, 894).

The in vitro activity of the compounds of the present invention at the5-HT_(1D) binding site may be determined according to the followingprocedure. Bovine caudate tissue is homogenized and suspended in 20volumes of a buffer containing 50 mM TRIS·hydrochloride(tris[hydroxymethyl]aminomethane hydrochloride) at a pH of 7.7. Thehomogenate is then centrifuged at 45,000G for 10 minutes. Thesupernatant is then discarded and the resulting pellet resuspended inapproximately 20 volumes of 50 mM TRIS·hydrochloride (HCl) buffer at pH7.7. This suspension is then pre-incubated for 15 minutes at 37° C.,after which the suspension is centrifuged again at 45,000G for 10minutes and the supernatant discarded. The resulting pellet(approximately 1 gram) is resuspended in 150 ml of a buffer of 15 mMTRIS·hydrochloride (HCl) containing 0.01 percent ascorbic acid with afinal pH of 7.7 and also containing 10 μM pargyline and 4 mM calciumchloride (CaCl₂). The suspension is kept on ice at least 30 minutesprior to use.

The inhibitor, control or vehicle is then incubated according to thefollowing procedure. To 50 μl of a 20 percent dimethylsulfoxide(DMSO)/80 percent distilled water solution is added 200 μl of tritiated5-hydroxytryptamine (2 nM) in a buffer of 50 mM TRIS·hydrochloridecontaining 0.01 percent ascorbic acid at pH 7.7 and also containing 10μM pargyline and 4 μM calcium chloride, plus 100 nM of 8-hydroxy-DPAT(dipropylaminotetraline) and 100 nM of mesulergine. To this mixture isadded 750 μl of bovine caudate tissue, and the resulting suspension isvortexed to ensure a homogenous suspension. The suspension is thenincubated in a shaking water bath for 30 minutes at 25° C. Afterincubation is complete, the suspension is filtered using glass fiberfilters (e.g., Whatman GF/B-filters™). The pellet is then washed threetimes with 4 ml of a buffer of 50 mM TRIS·hydrochloride at pH 7.7. Thepellet is then placed in a scintillation vial with 5 ml of scintillationfluid (aquasol 2 ™) and allowed to sit overnight. The percent inhibitioncan be calculated for each dose of the compound. An IC₅₀ value can thenbe calculated from the percent inhibition values.

The activity of the compounds of the present invention for 5-HT_(1A)binding ability can be determined according to the following procedure.Rat brain cortex tissue is homogenized and divided into samples of 1gram lots and diluted with 10 volumes of 0.32 M sucrose solution. Thesuspension is then centrifuged at 900G for 10 minutes and the supernateseparated and recentrifuged at 70,000G for 15 minutes. The supernate isdiscarded and the pellet re-suspended in 10 volumes of 15 mMTRIS·hydrochloride at pH 7.5. The suspension is allowed to incubate for15 minutes at 37° C. After pre-incubation is complete, the suspension iscentrifuged at 70,000G for 15 minutes and the supernate discarded. Theresulting tissue pellet is resuspended in a buffer of 50 mMTRIS·hydrochloride at pH 7.7 containing 4 mM of calcium chloride and0.01 percent ascorbic acid. The tissue is stored at −70° C. until readyfor an experiment. The tissue can be thawed immediately prior to use,diluted with 10 μm pargyline and kept on ice.

The tissue is then incubated according to the following procedure. Fiftymicroliters of control, inhibitor, or vehicle (1 percent DMSO finalconcentration) is prepared at various dosages. To this solution is added200 μl of tritiated DPAT at a concentration of 1.5 nM in a buffer of 50mM TRIS·hydrochloride at pH 7.7 containing 4 mM calcium chloride, 0.01percent ascorbic acid and pargyline. To this solution is then added 750μl of tissue and the resulting suspension is vortexed to ensurehomogeneity. The suspension is then incubated In a shaking water bathfor 30 minutes at 37° C. The solution is then filtered, washed twicewith 4 ml of 10 mM TRIS·hydrochloride at pH 7.5 containing 154 mM ofsodium chloride. The percent inhibition is calculated for each dose ofthe compound, control or vehicle. IC₅₀ values are calculated from thepercent inhibition values.

The compounds of formula I of the present Invention described in thefollowing Examples were assayed for 5-HT_(1A) and 5-HT_(1D) affinityusing the aforementioned procedures. All such compounds exhibited IC₅₀'sless than 0.60 μM for 5-HT_(1D) affinity and IC₅₀'s less than 1.0 μM for5-HT_(1A) affinity.

The agonist and antagonist activities of the compounds of the inventionat 5-HT_(1A) and 5-HT_(1D) receptors can be determined using a singlesaturating concentration according to the following procedure. MaleHartley guinea pigs are decapitated and 5-HT_(1A) receptors aredissected out of the hippocampus, while 5HT_(1D) receptors are obtainedby slicing at 350 mM on a McIlwain tissue chopper and dissecting out thesubstantia nigra from the appropriate slices. The individual tissues arehomogenized in 5 mM HEPES buffer containing 1 mM EGTA (pH 7.5) using ahand-held glass-Teflon® homogenizer and centrifuged at 35,000× g for 10minutes at 4° C. The pellets are resuspended in 100 mM HEPES buffercontaining 1 mM EGTA (pH 7.5) to a final protein concentration of 20 mg(hippocampus) or 5 mg (substantia nigra) of protein per tube. Thefollowing agents are added so that the reaction mix in each tubecontained 2.0 mM MgCl₂, 0.5 mM ATP, 1.0 mM CAMP, 0.5 mM IBMX, 10 mMphosphocreatine, 0.31 mg/mL creatine phosphokinase, 100 μM GTP and 0.5-1microcuries a[³²P]-ATP (30 Ci/mmol: NEG-003-New England Nuclear).Incubation is initiated by the addition of tissue to siliconizedmicrofuge tubes (in triplicate) at 30° C. for 15 minutes. Each tubereceives 20 μL tissue, 10 μL drug or buffer (at 10× finalconcentration), 10 μL 32 nM agonist or buffer (at 10× finalconcentration), 20 μL forskolin (3 μM final concentration) and 40 μL ofthe preceding reaction mix. Incubation is terminated by the addition of100 μL 2% SDS, 1.3 mM CAMP, 45 mM ATP solution containing 40,000 dpm[³H]-cAMP (30 Ci/mmol: NET-275-New England Nuclear) to monitor therecovery of CAMP from the columns. The separation of [³²P]-ATP and[³²P]-cAMP is accomplished using the method of Salomon et al.,Analytical Biochemistry, 1974, 58, 541-548. Radioactivity is quantifiedby liquid scintillation counting. Maximal inhibition is defined by 10 μM(R)-8-OH-DPAT for 5-HT_(1A) receptors, and 320 nM B-HT for 5-HT_(1D)receptors. Percent inhibitions by the test compounds are then calculatedin relation to the Inhibitory effect of (R)-8-OH-DPAT for 5-HT_(1A)receptors or 5-HT for 5-HT_(1D) receptors. The reversal of agonistInduced inhibition of forskolin-stimulated adenylate cyclase activity iscalculated in relation to the 32 nM agonist effect.

The compounds of the Invention can be tested for in vivo activity forantagonism of 5-HT_(1D) agonist-induced hypothermia in guinea pigsaccording to the following procedure.

Male Hartley guinea pigs from Charles River, weighing 250-275 grams onarrival and 300-600 grams at testing, serve as subjects in theexperiment. The guinea pigs are housed under standard laboratoryconditions on a 7 a.m. to 7 p.m. lighting schedule for at least sevendays prior to experimentation. Food and water are available ad libitumuntil the time of testing.

The compounds of the invention can be administered as solutions in avolume of 1 ml/kg. The vehicle used is varied depending on compoundsolubility. Test compounds are typically administered either sixtyminutes orally (p.o.) or 0 minutes subcutaneous (s.c.) prior to the5-HT_(1D) agonist, which is administered at a dose of 5.6 mg/kg, s.c.Before a first temperature reading is taken, each guinea pig is placedin a clear plastic shoe box containing wood chips and a metal grid floorand allowed to acclimate to the surroundings for 30 minutes. Animals arethen returned to the same shoe box after each temperature reading. Priorto each temperature measurement each animal is firmly held with one handfor a 30-second period. A digital thermometer with a small animal probeis used for temperature measurements. The probe is made of semi-flexiblenylon with an epoxy tip. The temperature probe is inserted 6 cm. intothe rectum and held there for 30 seconds or until a stable recording isobtained. Temperatures are then recorded.

In p.o. screening experiments, a “pre-drug” baseline temperature readingis made at −90 minutes, the test compound is given at −60 minutes and anadditional −30 minute reading is taken. The 5-HT_(1D) agonist is thenadministered at 0 minutes and temperatures are taken 30, 60, 120 and 240minutes later.

In subcutaneous screening experiments, a pre-drug baseline temperaturereading is made at −30 minutes. The test compound and 5-HT_(1D) agonistsare given concurrently and temperatures are taken at 30, 60, 120 and 240minutes later.

Data are analyzed with two-way analysis of variants with repeatedmeasures in Newman-Keuls post hoc analysis.

The active compounds of the invention can be evaluated as anti-migraineagents by testing the extent to which they mimic sumatriptan incontracting the dog isolated saphenous vein strip [P. P. A. Humphrey etal., Br. J. Pharmacol., 94, 1128 (1988)]. This effect can be blocked bymethiothepin, a known serotonin antagonist. Sumatriptan is known to beuseful in the treatment of migraine and produces a selective increase incarotid vascular resistance in the anesthetized dog. The pharmacologicalbasis of sumatriptan efficacy has been discussed in W. Fenwick et al.,Br. J. Pharmacol., 96, 83 (1989).

Serotonin 5HT₁ receptor affinity can be determined by the in vitroreceptor binding assays, as described for the 5HT_(1A) receptor usingrat cortex as the receptor source and [³H]-8-OH-DPAT as the radioligand[D. Hoyer et al. Eur. J. Pharm., 118, 13 (1985)] and as described forthe 5-HT_(1D) receptor using bovine caudate as the receptor source and[³H]serotonin as the radioligand [R. E. Heuring and S. J. Peroutka, J.Neuroscience, 7, 894 (1987)]. Of the active compounds tested, allexhibited an IC₅₀ in either assay of 1 μM or less.

The compounds of formula I may advantageously be used in conjunctionwith one or more other therapeutic agents, for instance, differentantidepressant agents such as tricyclic antidepressants (e.g.,amitriptyline, dothiepin, doxepin, trimipramine, butripyline,clomipramine, desipramine, imipramine, iprindole, lofepramine,nortriptyline or protriptyline), monoamine oxidase inhibitors (e.g.,isocarboxazid, pheneizine or tranylcyclopramine) or 5HT re-uptakeinhibitors (e.g., fluvoxamine, sertraline, fluoxetine or paroxetine),and/or with antiparkinsonian agents such as dopaminergicantiparkinsonian agents (e.g., levodopa, preferably in combination witha peripheral decarboxylase inhibitor e.g., benserazide or carbidopa, orwith a dopamine agonist e.g., bromocriptine, lysuride or pergolide). Itis to be understood that the present invention covers the use of acompound of general formula (I) or a physiologically acceptable salt orsolvate thereof in combination with one or more other therapeuticagents.

Compounds of the formula I and the pharmaceutically acceptable saltsthereof, in combination with a 5-HT re-uptake inhibitor (e.g.,fluvoxamine, sertraline, fluoxetine or paroxetine), preferablysertraline, or a pharmaceutically acceptable salt or polymorph thereof(the combination of a compound of formula I with a 5HT re-uptakeinhibitor is referred herein to as “the active combinations”), areuseful psychotherapeutics and may be used in the treatment or preventionof disorders the treatment or prevention of which is facilitated byenhanced serotonergic neurotransmission e.g., hypertension, depression,generalized anxiety disorder, phobias, posttraumatic stress syndrome,avoidant personality disorder, sexual dysfunction, eating disorders,obesity, chemical dependencies, cluster headache, migraine, pain,Alzheimer's disease, obsessive-compulsive disorder, panic disorder,memory disorders (e.g., dementia, amnestic disorders, and age-associatedmemory impairment), Parkinson's diseases (e.g., dementia in Parkinson'sdisease, neuroleptic-induced Parkinsonism and tardive dyskinesias),endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularlyin the cerebral vasculature), cerebellar ataxia, gastrointestinal tractdisorders involving changes in motility and secretion and chronicparoxysmal hemicrania and headache associated with vascular disorders.

Serotonin (5-HT) re-uptake inhibitors, preferably sertraline, exhibitpositive activity against depression; chemical dependencies; anxietydisorders including panic disorder, generalized anxiety disorder,agoraphobia, simple phobias, social phobia, and post-traumatic stressdisorder; obsessive-compulsive disorder; avoidant personality disorderand premature ejaculation in mammals, including humans, due in part totheir ability to block the synaptosomal uptake of serotonin.

U.S. Pat. No. 4,536,518 describes the synthesis, pharmaceuticalcomposition and use of sertraline for depression and is herebyincorporated by reference in its entirety.

Activity of the active combination as antidepressants and relatedpharmacological properties can be determined by methods (1)-(4) below,which are described In Koe, B. et al., Journal of Pharmacology andExperimental Therapeutics, 226 (3), 686-700 (1983). Specifically,activity can be determined by studying (1) their ability to affect theefforts of mice to escape from a swim-tank (Porsoft mouse “behaviordespair” test), (2) their ability to potentiate5-hydroxytryptophan-induced behavioral symptoms in mice in vivo, (3)their ability to antagonize the serotonin-depleting activity ofp-chloroamphetamine hydrochloride in rat brain in vivo, and (4) theirability to block the uptake of serotonin, norepinephrine and dopamine bysynaptosomal rat brain cells in vitro. The ability of the activecombination to counteract reserpine hypothermia in mice in vivo can bedetermined according to the methods described In U.S. Pat. No.4,029,731.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated In rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insulator may be formulated containing a powder mixof a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (e.g., migraine) is 0.1 to200 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to above(e.g., migraine) in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains 20 μg to 1000 μg ofthe compound of the invention. The overall daily dose with an aerosolwill be within the range 100 μg to 10 mg. Administration may be severaltimes daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or3 doses each time.

In connection with the use of an active compound of this invention witha 5-HT re-uptake inhibitor, preferably sertraline, for the treatment ofsubjects possessing any of the above conditions, it is to be noted thatthese compounds may be administered either alone or in combination withpharmaceutically acceptable carriers by either of the routes previouslyindicated, and that such administration can be carried out in bothsingle and multiple dosages. More particularly, the active combinationcan be administered In a wide variety of different dosage forms, i.e.,they may be combined with various pharmaceutically-acceptable inertcarriers in the form of tablets, capsules, lozenges, troches, hardcandies, powders, sprays, aqueous suspension, injectable solutions,elixirs, syrups, and the like. Such carriers include solid diluents orfillers, sterile aqueous media and various non-toxic organic solvents,etc. Moreover, such oral pharmaceutical formulations can be suitablysweetened and/or flavored by means of various agents of the typecommonly employed for such purposes. In general, the compounds offormula I are present In such dosage forms at concentration levelsranging from about 0.5% to about 90% by weight of the total composition,I.e., In amounts which are sufficient to provide the desired unit dosageand a 5-HT re-uptake inhibitor, preferably sertraline, is present insuch dosage forms at concentration levels ranging from about 0.5% toabout 90% by weight of the total composition, i.e., in amounts which aresufficient to provide the desired unit dosage.

A proposed daily dose of an active compound of this invention in thecombination formulation (a formulation containing an active compound ofthis invention and a 5-HT re-uptake inhibitor) for oral, parenteral,rectal or buccal administration to the average adult human for thetreatment of the conditions referred to above is from about 0.01 mg toabout 2000 mg, preferably from about 0.1 mg to about 200 mg of theactive ingredient of formula I per unit dose which could beadministered, for example, 1 to 4 times per day.

A proposed daily dose of a 5HT re-uptake inhibitor, preferablysertraline, in the combination formulation for oral, parenteral orbuccal administration to the average adult human for the treatment ofthe conditions referred to above is from about 0.1 mg to about 2000 mg,preferably from about 1 mg to about 200 mg of the 5-HT re-uptakeinhibitor per unit dose which could be administered, for example, 1 to 4times per day.

A preferred dose ratio of sertraline to an active compound of thisinvention In the combination formulation for oral, parenteral or buccaladministration to the average adult human for the treatment of theconditions referred to above is from about 0.00005 to about 20,000,preferably from about 0.25 to about 2,000.

Aerosol combination formulations for treatment of the conditionsreferred to above in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains from about 0.01 μgto about 1000 μg of the active compound of this invention, preferablyfrom about 1 μg to about 10 mg of such compound. Administration may beseveral times daily, for example 2, 3, 4 or 8 times, giving for example,1, 2 or 3 doses each time.

Aerosol formulations for treatment of the conditions referred to abovein the average adult human are preferably arranged so that each metereddose or “puff” of aerosol contains from about 0.01 mg to about 2000 mgof a 5-HT re-uptake Inhibitor, preferably sertraline, preferably fromabout 1 mg to about 200 mg of sertraline. Administration may be severaltimes daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or3 doses each time.

As previously indicated, a 5-HT re-uptake inhibitor, preferablysertraline, in combination with compounds of formula I are readilyadapted to therapeutic use as antidepressant agents. In general, theseantidepressant compositions containing a 5-HT re-uptake inhibitor,preferably sertraline, and a compound of formula I are normallyadministered in dosages ranging from about 0.01 mg to about 100 mg perkg of body weight per day of a 5-HT re-uptake inhibitor, preferablysertraline, preferably from about 0.1 mg. to about 10 mg per kg of bodyweight per day of sertraline; with from about 0.001 mg. to about 100 mgper kg of body weight per day of a compound of formula I, preferablyfrom about 0.01 mg to about 10 mg per kg of body weight per day of acompound of formula I, although variations will necessarily occurdepending upon the conditions of the subject being treated and theparticular route of administration chosen.

The following Examples illustrate the preparation of the compounds ofthe present invention. Melting points are uncorrected. NMR data arereported in parts per million (δ) and are referenced to the deuteriumlock signal from the sample solvent (deuteriochloroform unless otherwisespecified). Specific rotations were measured at room temperature usingthe sodium D line (589 nm). Commercial reagents were utilized withoutfurther purification. THF refers to tetrahydrofuran. DMF refers toN,N-dimethylformamide. Chromatography refers to column chromatographyperformed using 32-63 μm silica gel and executed under nitrogen pressure(flash chromatography) conditions. Room or ambient temperature refers to20-25° C. All non-aqueous reactions were run under a nitrogen atmospherefor convenience and to maximize yields. Concentration at reducedpressure means that a rotary evaporator was used.

EXAMPLE 13-[2-(4-Methylpiperazin-1-yl)-benzylidene]-1,3-dihydro-indol-2-one

Under nitrogen in a dry round bottom flask fitted with a condensor andmagnetic stir bar were placed 2-(4methyl-1-piperazinyl)-benzaldehyde(0.152 g, 0.75 g, 0.75 mmol), oxindole (0.104 g, 0.78 mmol) pyrrolidine(62 μL) and ethanol (7.0 mL). The mixture was heated to reflux for 16hours, cooled and evaporated under reduced pressure. The residue waspartitioned between ethyl acetate and water and the organic layer waswashed with saturated aqueous sodium chloride (NaCl), dried overmagnesium sulfate (MgSO₄)₁, filtered and absorbed onto 437 mg of silicagel. Elution with ethyl acetate (EtOAc) (125 mL), 1% methanol (CH₃OH) inEtOAc (100 mL), 2% CH₃OH in EtOAc (100 mL) and 4% CH₃OH+1% triethylamine(Et₃N) In EtOAc (50 mL) gave 280 mg of a yellow solid. Recrystallizationfrom hot CH₃OH gave the title product, m.p. 226-2280° C.

¹H NMR (CDCl₃, 250 MHz) δ 7.93 (1H, s) 7.84 (1H, br s), 7.79 (1H, dd),7.66 (1H, d, J=7.94 Hz), 7.42 (1H, dt), 7.12-7.03 (2H, m), 6.91-6.84(2H, m), 3.06 (4H, t), 2.66-2.53 (4H, m), 2.35 (3H, s).

Elemental Analysis: Calc'd for C₂₀H₂₁N₃O.0.5H₂O: C, 73.15; H, 6.75; N,12.79. Found: C, 73.00; H, 6.51; N, 13.01.

In the same manner the following analogs of Examples 2-6 were prepared:

EXAMPLE 26-Chloro-3-[2-(4-methlpiperazin-1-yl)-benzylidene]-1,3-dihydro-indol-2-oneHydrochloride Dihydrate

m.p. 265-267° C.(CH₂Cl₂).

PBMS: 354 (M⁺1).

Elemental Analysis calc'd for C₂₀H₂₀ClN₃O.HCl.2H₂O: C, 56.34; H, 5.91;N, 9.86. Found: C, 56.83; H, 5.90; N, 10.07.

EXAMPLE 31-Methyl-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1,3-dihydroindol-2-one Hydrochloride Hydrate

m.p. 120° C. decomp. (Et₂O:CH₂Cl₂).

PBMS: 334 (M⁺¹)

Elemental Analysis calc'd for C₂₁H₂₃N₃O.HCl.2.5H₂O: C, 60.79; H, 7.04;N, 10.13. Found: C, 61.04; H, 6.69; N, 10.18.

EXAMPLE 43-[2-(4-Methylpiperazin-1-yl)-benzylidene]-1-phenyl-1,3-dihydro-indol-2-one Hemihydrate

m.p. 171-172° C. (EtOAc).

PBMS: 396 (M⁺¹).

Elemental Analysis calc'd for C₂₅H₂₅N₃O.0.5 H₂O: C, 77.20; H, 6.48; N,10.39. Found: C, 77.31; H, 6.43; N, 10.39.

EXAMPLE 5 1-(3,4-Dichlorobenzyl)-3-[2-(4methylpiperazin-1-yl)-benzyl-idene]-1,3-dihydro-indol-2-one.

m.p. 120-124° C. (EtOAc: Hexanes).

PBMS: 478 (M⁺¹).

Elemental Analysis calc'd for C₂₇H₂₅Cl₂N₃O: C, 67.78; H, 5.27; N, 8.78.Found: C, 67.85; H, 5.41; N, 8.53.

EXAMPLE 65-Chloro-3-[2-(4methylpiperazin-1-yl)-benzylidene]-1,3-dihydro-indol-2-one

m.p. 235-2370° C. (MeOH).

PBMS 354 (M⁺¹).

Elemental Analysis calc'd for C₂₀H₂₀ClN₃O: C, 67.89; H, 5.70; N, 11.88.Found: C,67.39; H,5.67; N, 11.81.

EXAMPLE 71-(3,4-Dichlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-onehemidydrate

Under nitrogen in a 3-necked flask fitted with a stirrer, thermometerand condensor were added 12.8 g (0.321 mol) of NaH (60% oil dispersion)and 2165 mL of anhydrous THF. After cooling to 0° C., a solution of 48.8g (0.212 mol) of 1-(3,4-dichlorophenyl)-pyrrolidin-2-one and 42.7 g(0.209 mol) of 2-(4methyl-1-piperazinyl)-benzaldehyde in 1300 mL of THFwas added with ice bath cooling. Following the addition, the mixture washeated at reflux for 7 hours, then concentrated in vacuo to a dark brownresidue which was triturated with hot 10% EtOAc:hexanes. The remainingresidue was filtered and air-dried to 95.6 g of a tan solid which wasrecrystallized from 16 L of MeOH to yield 24.2 g of an off-white solid.Additional recrystallization from CHCl₃:MeOH gave the title product asan off-white solid, 14.4 g, m.p. 224-225° C.

PBMS: 416 (M⁺¹), 418, 420

¹H-NMR (CDCl₃, 250 MHz) δ 7.98 (1H, d, J=2.6 Hz), 7.82 (1H, t, J=2.7Hz), 7.70 (1H, dd), 7.48-7.41 (2H, m), 7.34 (1H, dt), 7.09 (2H, d, J=7.8Hz). 3.91 (2H, t, J-6.8 Hz), 3.23-3.14 (2H, m), 3.00 (4H, sym m), 2.63(4H, br s), 2.35 (3H, s).

Elemental Analysis: calc'd for C₂₂H₂₃N₃OCl₂.0.5H₂O: C, 62.12; H, 5.69;N, 9.88. Found: C, 62.06; H, 5.39; N, 9.69.

Additional crops of the title product were also isolated from the motherliquors retained from the recrystallizations.

The free base was converted to the hydrochloride salt by dissolving thebase in methanol and add 1 N HCl in Et₂O to precipitate the salt whichwas recrystallized from methanol: Et₂O to a white crystalline solid,m.p. 177-179° C.

Elemental Analysis calc'd. for C₂₂H₂₃N₃OCl₂.HCl.1.5H₂O: C, 55.07; H,5.67; N, 8.76. Found: C, 55.22; H, 5.61; N, 8.73.

By the same procedure, the following compounds of Examples 8-28 werealso prepared:

EXAMPLE 81-(2.4-Dichlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]pyrrolidin-2-one

m.p. 228-229° C.

PBMS: 416 (M⁺¹).

Elemental Analysis calc'd for C₂₂H₂₃N₃OCl₂: C, 63.47; H, 5.57; N, 10.09.Found: C, 63.30; H, 5.53; N, 10.12.

EXAMPLE 91-(3,4-Difluorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one

m.p. 228-229° C.

PBMS: 384 (M⁺¹).

Elemental Analysis calc'd for C₂₂H₂₃FN₃O.⅓H₂O: C, 67.85; H, 6.13; N,10.79. Found: C, 67.99; H, 6.02; N, 10.86.

EXAMPLE 101-(3,4Dichlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-onehemihydate

m.p. 228-229° C.

PBMS: 434 (M⁺¹).

Elemental Analysis calc'd for C₂₂H₂₂Cl₂FN₃O.0.5H₂O: C, 59.60; H, 5.23;N, 9.48. Found: C, 59.67; H, 5.02; N, 9.44.

EXAMPLE 111-(4Chlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one

m.p. 177-178° C. (EtOAc).

PBMS: 396 (M⁺¹).

EXAMPLE 121-(3,4-Dichlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one

m.p. 138-139.5° C. (EtOAc).

PBMS: 430 (M⁺¹).

EXAMPLE 131-(4-Chlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one

m.p. 158-159° C. (Et₂O).

PBMS: 414 (M⁺¹).

EXAMPLE 141-(3,4-Dichlorophenyl)-3-[5-fluoro-2-(4methylpiperazin-1-yl)-benzylidene]-piperidin-2-one

m.p. 161-162° C. (EtOAc)

PBMS: 448 (M⁺¹).

EXAMPLE 15 3-[2-(4-Methylpiperazin-1-yl)-benzylidene]-1phenylpyrrolidin-2-one

m.p. 178-179.5° C.

PBMS: 348 (M⁺¹).

Elemental Analysis calc'd for C₂₂H₂₅N₃O: C, 76.05; H, 7.25; N, 12.09.Found: C, 76.36; H, 6.90; N, 12.18.

EXAMPLE 163-[2-(4-Methylpiperazin-1-yl)-benzylidene]-1-(4-trifluoromethylphenyl)-pyrrolidin-2-one

m.p. 185-186.5° C.

PBMS: 416 (M⁺¹).

Elemental Analysis calc'd for C₂₃H₂₄F₃N₃O: C, 66.49; H, 5.82; N, 10.11.Found: C, 66.42; H, 5.85; N, 10.18.

EXAMPLE 173-[2-(4-Methylpiperazin-1-yl)-benzylidene]-1-tolyl-pyrrolidin-2-one

m.p. 165-167° C.

PBMS: 362 (M⁺¹).

Elemental Analysis calc'd for C₂₃H₂₇N₃O.0.25H₂O: C, 75.48; H, 7.57; N,11.48. Found: C, 75.68; H, 7.56; N, 11.39.

EXAMPLE 181-(4-Chlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one

m.p. 188-190° C.

PBMS: 382 (M⁺¹).

Elemental Analysis calc'd for C₂₂H₂₄ClN₃O.0.25 C₄H₈O₂: C, 68.39; H,6.49; N, 10.40. Found: C, 68.24; H, 6.62; N 10.18.

(compound contained ¼ mole of ethyl acetate)

EXAMPLE 193-[4Fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-1-phenylpyrrolidin-2-one

m.p. 199-200.5° C.

PBMS: 366 (M⁺¹).

EXAMPLE 201-(3,4-Dichlorophenyl)-3-[2-fluoro-6-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one

m.p. 170-171° C.

PBMS: 434 (M⁺¹).

Elemental Analysis calc'd for C₂₂H₂₂Cl₂FN₃O: C, 60.84; H, 5.11; N, 9.67.Found: C, 60.77; H, 5.07; N, 9.62.

EXAMPLE 211-(3,4-Difluorophenyl)-3-[5-fluoro-2(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one

m.p. 168-170° C. (MeOH:Et₂O).

PBMS: 416 (M⁺¹).

EXAMPLE 221-[2-(4Chlorophenyl)ethyl]-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one

m.p. 88-90° C. (Et₂O).

PBMS: 442 (M⁺¹).

EXAMPLE 231-(4-Chlorobenzyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one

m.p. 129-130° C.

PBMS: 396 (M⁺¹).

EXAMPLE 241-(4-Chlorobenzyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2one

m.p. 131-132° C.

PBMS: 414 (M⁺¹).

EXAMPLE 251-(3,4-Dichlorobenzyl)-3-[2-(4-methylpiperazin-1-yl)-benzyl]-idene]-pyrrolidin-2-one

m.p. 118-119° C.

PBMS: 430 (M⁺¹).

Elemental Analysis calc'd for C₂₃H₂₅Cl₂N₃O.0.25H₂O: C, 63.52; H, 5.91;N, 9.66. Found: C, 63.38; H, 5.85; N, 9.67.

EXAMPLE 261-(3,4-Dichlorobenzyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one

PBMS: 444 (M⁺¹).

EXAMPLE 271-(3,4-Dichlorophenyl)-3-[2-(2-dimethylaminoethoxy)-benzylidene]-pyrrolidin-2one

m.p. 111-112° C. (free base), 241-242° C. (HCl salt).

PBMS: 405 (M⁺¹).

Elemental Analysis calc'd for C₂₁H₂₂Cl₂N₂O₂: C, 62.23; H, 5.47; N, 6.91.Found: C, 62.42; H, 5.46; N, 6.86.

EXAMPLE 281-(3,4-Dichlorophenyl)-3-[5-methyl-2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2one

m.p. 149-150° C.

PBMS: 430 (M⁺¹).

EXAMPLE 291-(3,4-Difluorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzyl]-pyrrolidin-2-one

A mixture of1-(3,4-difluorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one(125 mg, 0.326 mmol), ammonium formate (411 mg, 6.53 mmol) and 10%palladium on carbon (40 mg) in 30 mL of anhydrous methanol was refluxedunder nitrogen for 18 hours. After cooling, the catalyst was removed Invacuo and the residue was treated with saturated aqueous sodiumbicarbonate and methylene chloride. The organic layer was removed,combined with a second extraction of the aqueous layer with additionalmethylene chloride, washed with saturated aqueous sodium chloride (NaCl)and dried. The solvent was again removed In vacuo to give the crudeproduct as a white solid (111 mg). This solid was dissolved in hot ethylacetate and crystallized by the addition of a few drops of hexanes. Thetitle product, 29 mg, has m.p. 130-131° C. From the filtrate a secondcrop of product was also obtained as above, 50 mg, mp. 130-131° C.

Mass spectrum: 386 (M⁺¹).

¹H-NMR (CDCl₃, 250 MHz) δ 7.75 (1H, m), 7.33-7.00 (6H, m), 3.71-3.60(2H, m) 3.39 (1H, dd, J=13.5, 4.2 Hz), 3.08 (1H, m), 2.93 (4H, dd,J=8.8, 4.2 Hz), 2.78 (1H, dd, J=13.5, 10.2 Hz), 2.59 (4H, br s), 2.36(3H, s), 2.17-2.01 (1H, m), 1.94-1.76 (1H, m).

Elemental Analysis: Calc'd for C₂₂H₂₅F₂N₃O: C, 68.55; H, 6.54; N, 10.90.Found: C, 68.55; H, 6.53; N, 10.90.

EXAMPLE 303-[2-(4-Methylpiperazin-1-yl)-benzyl]-1-phenyl-pyrrolidin-2-one

In a manner similar to the procedure of Example 29,3-[2-(4methylpiperazin-1-yl)-benzylidene]-1-phenyl-pyrrolidin-2-one wasconverted to3-[2-(4-methylpiperazin-1-yl)-benzyl]-1-phenyl-pyrrolidin-2-one, m.p.104-105.5° C.

Mass spectrum: 350 (M⁺¹).

¹H-NMR (CDCl₃, 250 MHz) δ 7.68 (2H, dd, J=8.7, 1.1 Hz), 7.39 (2H, t),7.26-7.03 (5H, m), 3.76-3.69 (2H, m), 3.40 (1H, dd, J=13.5, 3.9 Hz),3.06 (1H, m), 2.96 (4H, dd, J=5.2, 3.5 Hz), 2.81 (1H, dd, J=13.5, 3.9Hz), 2.59 (4H, br s), 2.36 (3H, s), 2.16-2.00 (1H, m), 1.94-1.76 (1H,m).

EXAMPLE 313-[2-(4-methylpiperazin-1-yl)-benzyl]-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-oneHydrochloride hemihydrate

3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1-(4-trifluoromethylphenyl)-pyrrolidin-2-onewas converted to3-[2-(4methylpiperazin-1-yl)-benzyl]-1-(4-trifluoromethylphenyl)-pyrrolidin-2-one hydrochloride hemihydrate, m.p. 181-183° C.

Mass spectrum: 418 (M⁺¹).

¹H-NMR (DMSO-d₆, 250 MHz) δ 10.61 (1H, br s), 7.91 (2H, d, J=8.5 Hz)7.72 (2H, d, J=8.9 Hz), 7.307.18 (2H, m), 7.18-7.03 (2H, m), 3.73 (2H,t, J=6.7 Hz), 3.50-3.33 (2H, m), 3.22-2.94 (8H, m), 2.78 (3H, s), 2.70(1H, dd, J=13.7, 10.2 Hz), 2.03 (1H, m), 1.74 (1H, m).

Elemental Analysis: Calc'd for C₂₃H₂₆N₃OF₃.HCl.½H₂O: C, 59.67, H, 6.10,N, 9.08. Found: C, 59.84; H, 6.06; N, 8.96.

EXAMPLE 321-[3,4Dichlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzyl]-piperidin-2-oneHydrochloride

A solution of1-(3,4-dichlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one(260 mg, 0.60 mmol) in 20 mL of methanol was combined with 100 mg of 10%palladium on carbon and hydrogenated on a Parr Shaker apparatus at 50psi for a total of 4 hours. The catalyst was then removed by filtrationthough diatomaceous earth and the solvent was removed in vacuo to give ayellow gummy residue. Chromatography (silica gel) eluting with 5%methanol (CH₃OH)/95% methylene chloride (CH₂Cl₂) gave clean product, 70mg, as a clear gum which was dissolved in dry ethyl ether (Et₂O) andtreated with HCl saturated ethyl ether to produce the hydrochloridesalt, 61 mg, m.p. 106-108° C.

Mass spectrum: 432 (M⁺¹), 434.

EXAMPLE 331-[3,4-Dichlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzyl]-piperidin-2-oneHydrochloride

Using a procedure similar to that of Example 32,1-(3,4-dichlorophenyl)-3[5fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one(270 mg, 0.6 mmol) was reduced after 18 hours to give, after conversionto the hydrochloride salt,1-[3,4-dichlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzyl]-piperidin-2-onehydrochloride, m.p. 83-85° C., white solid.

Mass spectrum: 450 (M⁺¹), 452.

1. A compound of the formula I, depicted below,

wherein R¹ is a group of the formula G¹, depicted below,

wherein R⁶ independently selected from hydrogen, (C₁-C₈) alkyl,[(C₂-C₄)alkyl]aryl wherein the aryl moiety is phenyl or naphthyl, andwherein said aryl moiety may optionally be substituted with one or moresubstituents independently selected from chloro, fluoro, bromo, iodo,(C₁-C₆)alkyl, (C₁-C₈)alkoxy, trifluoromethyl, cyano andSO_(g)(C₁-C₅)alkyl wherein g is zero, one or two; x is zero to eight;each R¹³ is, independently, (C₁-C₄)alkyl; R² is hydrogen, (C₁-C₄)alkyl,phenyl or naphthyl, wherein said phenyl or naphthyl may optionally besustituted with one or more substituents independently selected fromchloro, fluoro, brom, iodo, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, trifuoromethyl,cyano and SO_(g)(C₁-C₆)alkyl wherein g is zero, one or two; R³ is(CH₂)_(m)B, wherein m is zero, one, two or three and B is hydrogen,phenyl or naphthyl and wherein each of the foregoing phenyl and naphthylgroups may optionally be substituted with one or more substituentsindependently selected from chloro, fluoro, bromo, iodo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, trifluoromethyl, cyano hydroxy, COOH andSO_(g)(C₁-C₆)alkyl wherein g is zero, one or two; Z is CR⁴R⁵, wherein R⁴and R⁵ are independently selected from hydrogen, (C₁-C₆)alkyl andtrifluoromethyl; or Z is a combination one CR⁴R⁵ and a phenylene ornaphthylene wherein two adjacent ring members of said phenylene ornaphthylene are also members of ring A; X is hydrogen, chloro, fluoro,bromo, iodo, cyano, (C₁-C₆)alkyl, hydroxy, trifluoromethyl,(C₁-C₆)alkoxy, —SO_(g)(C₁-C₆)alkyl wherein g is zero one or two, CO₂R¹⁰or CONR¹¹R¹²; each of R¹⁰, R¹¹ and R¹² is selected, independently, fromthe radicals set forth in the definition of R²; n is three; and thebroken line indicates an optional double bond; with the proviso thatwhen Z is a combination of one CR⁴R⁵ and a phenylene or naphthylenewherein two adjacent ring members of said phenylene or naphtylene arealso members of ring A then n is 1; or a pharmaceutically acceptablesalt thereof.
 2. A compound according to claim 1 wherein Z is CH₂.
 3. Acompound according to claim 1, wherein R³ is substituted phenyl.
 4. Acompound according to claim 1, wherein said compound is selected from:1-(4-chlorobenzyl)-3-[2-(4methylpiperazin-1-yl)-benzylidene]-piperidin-2-one;1-(3,4-dichlorobenzyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one;1-(4-chlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one;1-(3,4-dichlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one;3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one;1-(3,4-dichlorophenyl)-3-[2-(4methylpiperazin-1-yl)-benzyl]-piperdin-2-one;1-(4-methoxyphenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-3,4dihydro-1H-quinolin-2-one;1-(3,4-dichlorophenyl)-3-[5-fluoro-2-(4methylpiperazin-1-yl)-benzyl]-piperdin-2one;1-(3,4-difluorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one;1-[2-(4-chlorophenyl)ethyl]-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-piperdin-2-one;and the pharmaceutically acceptable salts of such compounds.
 5. Apharmaceutical composition for treating or preventing a disorder orcondition selected from depression, generalized anxiety disorder,phobias, posttraumatic stress syndrome, obsessive-compulsive disorder,and panic disorder in a mammal, comprising an amount of a compoundaccording to claim 1 that is effective in treating or preventing suchdisorder or condition and a pharmaceutically acceptable carrier.
 6. Amethod for treating or preventing a disorder or condition selected fromdepression, generalized anxiety disorder, phobias, posttraumatic stresssyndrome, obsessive-compulsive disorder, and panic disorder in a mammal,comprising administering to a mammal in need of such treatment orprevention an amount of a compound according to claim 1 that iseffective in treating or preventing such disorder or condition.